Bestmann-Ohira Reagent: Synthesis of Alkynes from Aldehydes Protocol

Acetylene chemistry has been and remains an important constituent element of molecular sciences. Its potential and widespread applications extend from organic synthesis through materials science to bioorganic chemistry. Some examples are enediynes (DNA-cleaving agents), ‘click chemistry’ tools and building blocks. Consequently, it triggers a demand for efficient syntheses of alkynes.

Dimethyldiazomethylphosphonate (DAMP) has been utilized as a reagent for the synthesis of alkynes from aldehydes.1 This method is a widely used alternative to the longer known Corey–Fuchs method2 and related procedures.3 The major disadvantage with DAMP, is that the reagent should be prepared freshly and isolated prior to metallation with KOtBu at low temperatures under an inert gas atmosphere. Corey–Fuchs method involves the Wittig-Reactions yielding 1,1-dibromoolefins, and subsequent elimination of hydrogenhalide. These two step procedures require the use of strong bases usually at low temperatures an inert gas atmosphere. To address the above deficiencies, Bestmann reported a more environmentally friendly protocol for alkyne synthesis from aldehydes using dimethyl (1-diazo-2-oxopropyl) phosphonate in one-pot (Scheme 1).4

Scheme 1: One-pot synthesis of alkynes from aldehydes.

Special Hazards: Corrosives, Irritants, and Flammables (Note: For a comprehensive understanding of all associated hazards, refer to each component’s MSDS by MatNo).

General experimental procedure:

Assemble a 50 mL 3-neck reaction flask with condenser topped with a large bore stopcock leading to argon bubbler and thermometer.

Flush the flask with argon for 30 minutes.

Charge the aldehyde using a syringe and potassium carbonate using a powder funnel into the reaction flask under argon pressure.

Degas the solids by evacuating and backfilling with argon for a total of three cycles; afterwards place the reaction flask under a slight positive pressure of argon.

1-Chloro-4-ethynylbenzene: 4-Chlorobenzaldehyde and potassium carbonate were placed in an oven dried round bottom flask. Vacuum was applied and the flask was then filled with argon (repeated twice). Anhydrous methanol was added and the mixture was stirred at room temperature under an argon atmosphere for 30 min. Dimethyl (1-diazo-2-oxopropyl)phosphonate solution (10% in acetonitrile) was added to the faint grey turbid reaction mixture. The mixture was stirred at room temperature under an argon atmosphere for 4 hours. The reaction was monitored by thin layer chromatography. The reaction mixture was diluted with ether and washed with aqueous sodium bicarbonate (5%) and dried over sodium sulfate. Solvent was evaporated to obtain 1-chloro-4-ethynylbenzene.

With the optimized conditions in hand, we then applied this methodology to other aldehydes (Scheme 3) containing sulfur heterocycles (eq. 1) and aliphatic chains (eq. 2) to study the scope and limitations of this method.